Transforming the Atopic Dermatitis Space
A deep dive into the evolving JAK paradigm, with a special focus on topicals
- November 2022
Bhavani Nelavelly and Ateeb Ali Khan, Research Managers, and Dr. Gaurav Sharma, Director
Introduction
Atopic dermatitis has the highest disease burden among skin diseases and ranks 15th among non-fatal diseases globally
The chronic inflammatory skin disease atopic dermatitis (AD), caused in part by underlying inflammation driven by an overactive immune system, can lead to itchy red patches, dry, scaly or thickened skin, and open, oozing, crusty sores. AD is a lifelong condition with no cure, so the current goal of care is to provide symptomatic relief (reduced pruritus and inflammation), restore skin barrier function and improve quality of life.
Although the condition affects all ages, it is most common in infants and children, with a worldwide lifetime prevalence of 15-20% compared to 1-3% in adults¹. AD can be classified as either mild-to-moderate or moderate-to-severe; globally, the mild-to-moderate form of the disease is more prevalent than the moderate-to-severe form. Although AD is not life-threatening, it has a huge impact on quality of life and constitutes a significant economic burden. Comorbidities include asthma, food allergy, allergic rhinitis and a predisposition to cutaneous infections. Children with AD also experience more significant psychosocial and behavioral issues compared with their peers. Patients with inadequately controlled moderate-to-severe AD experience debilitating symptoms despite the available treatment options.
AD Current and Forecasted Market Size
The US market alone could account for more than 80% of global sales in AD by the end of this decade
AD affects up to 20% of children and 3% of adults worldwide, and the prevalence of the disease appears to be increasing. The global AD market will experience significant growth in the near future, with global sales expected to increase from $6.4 billion in 2020 to $16.7 billion in 2030, representing a 10-year compound annual growth rate (CAGR) of 10.1%². The US is currently the largest market for AD. In 2020, US drug sales were worth approximately $5.0 billion, or 77.8% of the total AD market. By 2030², US sales are expected to grow to $13.5 billion and account for 80.7% of global sales. The major drivers of growth include the high rate of diagnosis and the increased availability of treatment options across all age groups and severities, as well as the high costs of biologics and Janus kinase inhibitors (JAKis).
Current AD treatment options include topical corticosteroids (TCS), immunomodulators, biologics and oral or topical JAK inhibitors. While systemic agents are paving the way in the treatment of moderate-to-severe disease, the arrival of new topical agents may diversify the mild-to-moderate treatment landscape. These include new topical JAK inhibitors which, it is hoped, will address the unmet need in this segment for better long-term disease control, with a lesser side-effect burden than TCS medications and topical calcineurin inhibitors (TCIs). Despite a class-wide boxed warning, Incyte’s Opzelura (ruxolitinib) – the first topical JAK inhibitor to be approved – has had a successful launch so far in the US and is expected to reach peak US sales of $1.5 billion in eczema alone³. A label expansion for biologic agents and JAK inhibitors to treat pediatric and adolescent AD patients could also be a key growth driver.
JAK Inhibitors
Exciting New Prospects in AD Treatment
JAK inhibitors have paved a new path in AD treatment that was previously dominated by broad-acting immunomodulatory agents such as cyclosporine, methotrexate and azathioprine. As an upstream regulator of cytokine secretion and immune activation, JAK inhibition blocks the function of multiple cytokines that are implicated in both pathogenesis and disease progression. And since JAK inhibitors target individual receptor-associated kinases, they also prevent the mediation of inflammatory signals in AD.
JAK inhibitors have garnered a lot of attention lately due to their high efficacy rates. The first approved asset was Pfizer’s tofacitinib, Xeljanz, originally developed for rheumatoid arthritis, in 2012. Since then, JAK inhibition has emerged as a promising MOA that can be used either systemically as oral drugs, or locally as topical formulation in dermatology.
JAKi Clinical Development Landscape
A total of five JAK inhibitors, spanning the mild-to-moderate and moderate-to-severe patient segments, were approved as of May 2022. Of these, oral JAK inhibitors have been in the picture longest; topical JAK inhibitors, on the other hand, have only just entered the treatment paradigm with the approval of Incyte’s Opzelura. A further five oral and five topical assets are in clinical development, but the latter are slightly further ahead, with three topical assets and two oral assets in Phase II.
A deep-dive analysis of JAK inhibitor subtypes suggests that selective JAK-1 inhibitors are being investigated the most extensively in AD; together with JAK-1/2 inhibitors, this subtype constitutes around 60% of the JAK inhibitors in clinical development for AD.
The JAK-1/2 subtype, of which Opzelura is an example, is the most prevalent among topical assets. Roivant’s dual JAK/SYK pathway inhibitor, cerdulatinib, and VYNE Therapeutics’ JAK inhibitor/S1P receptor modulator, FMX-114, are unique topical JAK inhibitors that also target non-JAK pathways.
The JAK inhibitor landscape in AD as of May 2022 is as follows:
Oral JAK inhibitors are well-positioned to target the moderate-to-severe AD patient population, while topical JAK inhibitors are largely either approved or being investigated in patients with mild-to-moderate AD, with the exception of Aclaris’ ATI-1777, which is being tested in moderate-to-severe patients. The only JAK inhibitor that caters to both patient populations is Japan Tobacco’s Corectim (delgocitinib) ointment, which is currently only approved in Japan.
Reistone’s SHR0302 and Suzhou Zelgen’s jaktinib are being evaluated as both oral and topical formulations for moderate-to-severe and mild-to-moderate AD, respectively, while VYNE Therapeutics’ FMX114, a fixed-dose combination (FDC) of tofacitinib and fingolimod, is being tested in a Phase I/II trial in Australia and is the only FDC in the entire AD landscape.
Geographical analysis suggests that development activity involving JAK inhibitors is the most dense in the rest of the world (RoW) region, which encompasses emerging markets such as China. More than 45% of all approved assets and 70% of developmental assets belong to Chinese biotech companies, suggesting that China will be a major contributor to the JAK inhibitor market in this space. No asset is being developed solely in the EU.
JAKi Clinical Development Trends
The phase-wise distribution of JAK inhibitor trials (updated as of May 2022) highlights the high-density areas of development:
Considering only active and soon-to-start trials, the greatest trial activity can be observed at Phase III, where there is three times the level of activity than at Phase I. Compared to oral JAK inhibitors, the increase in trial activity from Phase II to Phase III is much more prominent for topical JAK inhibitors, for which the number of Phase III trials is double that of Phase II trials. Further asset-based analysis of JAK inhibitor trials reveals that, of ongoing and planned trials, AbbVie has the highest number of trials for Rinvoq, followed by Eli Lilly for Olumiant and Incyte for Opzelura. These top three assets, all approved within the past two years, constitute roughly 50% of the entire clinical trial activity spectrum within the JAK inhibitor domain. This indicates that most of the ongoing and planned clinical activity is due to the life cycle management strategies of companies with approved products. For instance, in addition to AD, Opzelura and Corectim are also being investigated in chronic hand eczema, a type of eczema that can arise due to various conditions, such as contact dermatitis or atopic dermatitis. Furthermore, Opzelura is the topical therapy with the most clinical trial activity, suggesting that most of the current activity is for oral JAK inhibitors. Meanwhile, the number of active and planned Phase III trials for the pediatric population is more than double the number of Phase I and Phase II trials combined, which is mainly due to Rinvoq’s ongoing trials covering both pediatric and adult age groups.
Comparison of Topical JAKis with Oral JAKis and Non-JAKi Therapies
Efficacy and Safety Comparison Between Topical JAKis and Oral JAKis
Efficacy: Performance on IGA and EASI endpoints
An analysis of subgroups pooled from studies within a meta-analysis showed that both oral and topical JAK inhibitors demonstrated significant improvements in both Investigator Global Assessment (IGA) and Eczema Area and Severity Index (EASI) scores. The greatest reduction in IGA scores with topical JAK inhibitors was seen at an earlier timepoint than that with oral JAK inhibitors (Week 2 (RR: 3.53, 95% CI: 1.43 to 8.73, p=0.006) vs. Week 4 (RR: 3.65, 95% CI: 2.53 to 5.27, p<0.001))⁴.
In patients with baseline moderate-to-severe disease, topical JAK inhibitors demonstrated a greater EASI response compared to oral JAK inhibitors (topical: WMD (weighted mean difference): -44.16, 95% CI: -54.69 to -33.63, p<0.001; oral: WMD: -37.66, 95% CI: -49.06 to -26.27, p<0.001)⁴. Topical JAK inhibitors were significantly more efficacious than oral inhibitors, but almost all the topical JAK inhibitors in active development are positioned to target the mild-to-moderate patient population, in which a smaller body surface area (BSA; <20%) is affected by the disease.
Meanwhile, at an asset level, Cibinqo showed the most significant improvement in IGA response compared to placebo/vehicle (RR: 5.47, 95% CI: 2.74 to 10.93, p<0.001), and Rinvoq provided the largest significant reduction in EASI score compared to placebo/vehicle at Week 4 (WMD: -53.92, 95% CI: -69.26 to -38.58, p<0.001)⁴.
Safety
Data from another meta-analysis revealed that the topical JAK inhibitors Opzelura and Corectim caused fewer treatment-emergent adverse events (TEAEs) than other JAK inhibitors. Nasopharyngitis was the most common AE, followed by upper respiratory tract infections. These occurred most frequently with selective oral JAK-1 inhibitors such as abrocitinib and upadacitinib; the lowest rate of occurrence was with Opzelura. Abrocitinib was also found to have a higher rate of TEAEs than placebo (RR: 1.25, 95% CI: 1.10 to 1.42, p=0.001)⁴. Lower risk of serious infections, major adverse cardiovascular events (MACE), thrombosis and malignancies, indicates that topical JAK inhibitors may serve as better therapeutic options than oral JAK inhibitors due to their superior safety profile. KOLs have also noted that the safety issues surrounding JAK inhibitors are less likely with topical agents because of the limited systemic exposure associated with them, and that the safety concerns with oral JAK inhibitors could benefit topical JAK inhibitors.
Regarding Opzelura specifically, dermatologists have said that its black box warning pertains to the entire class of JAK inhibitors and is not specifically directed to Opzelura itself. Opzelura’s pharmacokinetic data do not present any concern about systemic absorption, as only 6% of the drug is absorbed. In patients with an affected BSA of <20%, plasma concentrations are about 90% lower than with oral exposure. The most critical AEs, malignancy and serious infections, have not been observed with the use of Opzelura, and laboratory testing is not required with this drug unlike with oral JAK inhibitors.
Potential Benefits of Topical JAKis Over Other Therapies
Topical JAK inhibitors are devoid of the skin thinning and growth issues associated with TCS and can be used for longer than two to three weeks, as up to eight weeks’ usage has been studied in trials. Furthermore, they do not have the patient adherence issues associated with steroid treatment, and unlike non-steroidal therapies such as Eucrisa, their usage is generally well tolerated and unaccompanied by a stinging or burning sensation. Their onset of action is also very fast, almost steroid-like, in comparison to biologics. According to some KOLs, Opzelura is the fastest, most effective non-steroidal topical AD treatment.
Both topical and oral JAK inhibitors also offer ease of administration compared to injectable systemic therapies, which are intended for use under the guidance of a healthcare provider and require caregivers and patients to have proper training. They also offer a preferred option for needle-phobic patients.
Furthermore, multiple laboratory tests are recommended prior to initiating treatment with oral JAK inhibitors, but minimal monitoring and testing is required with topical assets. Therefore, it can be assumed that treatment with topical JAK inhibitors is cheaper for patients than oral JAK inhibitors.
Commercialization of JAK Inhibitors
Commercialization, Messaging and Patient Support Programs for Topical JAKis
Opzelura has been launched as the first and only topical JAK inhibitor for AD in the US market, carrying a detailed class-wide warning applicable to all JAK inhibitors, as mandated by the FDA. The messaging strategy for Opzelura is built upon highlighting its uniqueness in being the only FDA-approved topical JAK inhibitor and also addressing the patients’ concern over “steroid-phobia”.
Opzelura can be accessed by AD patients in the US through co-pay savings programs meant for commercially insured patients, commercial access programs and patient assistance programs, IncyteCARES, which caters to both the uninsured and underinsured patients where they are not required to bear any out-of-pocket costs.
Opzelura’s uptake since its launch in the US has been robust, with over 68,000 total prescriptions and first-quarter sales of $13 million5. Six months after launch, it achieved a new patient share of 12%, exceeding that of Eucrisa and Dupixent, and as at April 2022, a total of 146 million patients had received commercial, federal government and Medicaid insurance coverage for Opzelura use⁵.
Incyte also recently opened a second manufacturing site and implemented a new manufacturing process to improve the dissolution of Opzelura’s API and address texture complaints from consumers. The company is now preparing to reintroduce product samples in the US.
Competitive Assessment, Messaging and Patient Support Programs for Oral JAKis
Only three oral JAKs have been approved in AD so far: Olumiant, Rinvoq and Cibinqo, and the manufacturers of all three drugs – Eli Lilly, AbbVie and Pfizer, respectively – have strong presences in the immunology domain. Of these, Olumiant and Rinvoq have the strongest profiles, having both been approved for other autoimmune conditions associated with AD, such as rheumatoid arthritis; however, Olumiant’s approval in AD is restricted to the EU.
Rinvoq’s messaging strategy centers on its convenient, once-a-day oral dosing for pediatrics and adults, and its efficacy in skin clearance and itch reduction. The messaging for Cibinqo is similar, but Cibinqo is approved for use in adults only. For Cibinqo, Pfizer has adopted the slogan “not an injection or cream. 100% steroid-free”, which highlights the treatment’s ease of administration and non-steroidal formulation.
Under AbbVie’s Rinvoq Complete program, commercially insured patients pay as little as $5 per visit for lab tests and monitoring. The program also offers one-to-one support from insurance specialists and nurse ambassadors and enables early start of AD treatment with Rinvoq. Meanwhile, Pfizer’s dermatology patient-access program for Cibinqo enables commercially insured patients to pay as little as $0 with a co-pay savings card, as well as providing access to a live support representative who can help in exploring financial assistance options.
Access to novel agents in AD, such as oral JAK inhibitors, is limited due to the following factors:
- Payers may restrict prescriptions to specialists, such as dermatologists and allergists, because the use of JAK inhibitors may require knowledge that primary care physicians do not have
- Patients without health insurance coverage may struggle to access these therapies. Due to the high cost of newer agents and high out-of-pocket costs, patients may use cheaper, generic corticosteroids rather than the more effective JAK inhibitors
- Payers often require a 30-day trial of topical TCS or TCI therapy before other novel therapies can even be considered, which acts as a roadblock to the timely management of AD patients
Physicians’ Views on Prescribing JAK Inhibitors
When dermatologists were surveyed on the introduction of JAK inhibitors in the US, it was found that physicians intend to prescribe Opzelura to 15% of mild-to-moderate AD patients over the next year, and to 20% of patients over the next three years, with most of this usage expected to occur at the expense of TCS. The treatment duration for Opzelura is expected to be around seven months, compared to eight to nine months for other therapies, and is expected to perform better than Eucrisa in terms of efficacy, tolerability and marketing support. However, Eucrisa is viewed more favorably in terms of its safety and price⁶. Accordingly, the surveyed dermatologists indicated that they would be more willing to prescribe Opzelura if it had not been approved with a black box warning.
As far as oral JAK inhibitors are concerned, physicians showed a slight inclination towards Rinvoq over Cibinqo in terms of future prescription preference over the next three years (55% vs. 45%).
The Road Ahead
Currently, Opzelura is positioned to treat non-immunocompromised, mild-to-moderate AD patients who are 12 years of age and older who have had inadequate responses to other prescribed topical therapies. However, this does not mean that all upcoming topical JAK inhibitors will follow the same pattern. In fact, there are therapies in the pipeline – albeit only a few such as ATI-1777 – that are being positioned to target the moderate-to-severe form of the disease. ATI-1777 is also being considered for possible administration in combination with biologics to improve efficacy.
Some KOLs believe that topical JAK inhibitors could replace TCS, especially when it comes to application around sensitive areas, such as around the eyes or the very delicate skin in flexural areas or folds. Since there are safety concerns surrounding the long-term use of TCS, topical JAK inhibitors could also be prescribed as maintenance treatment to help preserve the response produced by TCS. They could also be utilized in patients who have experienced good symptomatic control but still have some itching at night. In these patients, continued TCS use would not be wise; meanwhile, for example, Opzelura has shown a greater than 4-point improvement in Itch NRS as early as Day 3, and in more than 50% of patients at Week 8.
Competitor Analysis
Conclusion
Atopic dermatitis is a heterogeneous, chronic inflammatory disorder of the skin that more commonly affects children than adults and if left untreated, can severely impact patients’ quality of life. With the landscape growing faster than ever due to the recent influx of JAK inhibitors, the global sales market for AD drugs is set to grow by about $10 billion from 2020 to 2030.
The arrival of JAK inhibitors in the AD market has catalyzed a rapid expansion of the treatment paradigm that had been stagnant since the approval of Dupixent back in 2017.
The number of approved oral JAKis therapies is greater than the number of approved topical therapies, with Opzelura being the only representative of the topical JAK inhibitor class in the US. Selective JAK-1 inhibitors, along with JAK-1/2 subtypes, constitute the bulk of JAK inhibitor subtypes in the landscape. Life cycle management strategies that aim to expand the patient reach for approved therapies have meant that the clinical activity spectrum is dominated by approved JAK inhibitors, with AbbVie being the most active in the space with several planned or active trials running for Rinvoq.
Topical JAK inhibitors mainly cater to the mild-to-moderate segment, with a few exceptions such as ATI-1777, which is intended to address the moderate-to-severe population. From a geographical standpoint, it is hard to ignore China’s increasing involvement in the development of in-house JAK candidates.
Although topical JAK inhibitors are positioned to treat the mild-to-moderate population with a BSA of <20%, studies have suggested that topical JAK inhibitors are more effective than oral JAK inhibitors in moderate-to-severe AD. In addition, despite the same black box warning being on the labels of both oral and topical JAK inhibitors, physicians understand that in the real world, these issues will not be much of a concern for topical therapies. However, it could be argued that the market uptake of topical JAK inhibitors would have been greater, had they been approved without a black box warning.
Despite the many advertisements released by manufacturers, access to novel JAK inhibitors is limited by factors such as high pricing, lack of insurance and payer restrictions.
The story of topical JAK inhibitors in the AD treatment landscape has just begun. Opzelura and other upcoming topical JAK inhibitors are expected to greatly diminish the use of TCS, if not completely replace them. A single topical JAK inhibitor can be used as top-to-bottom treatment irrespective of the application site, while steroid use requires that agents be regularly switched at a frequency based on the sensitivity of the application site, a significant issue that could alter the treatment paradigm reliant on TCS. Further, although there are other, non-JAK inhibitor topical agents that could compete with Opzelura, they have their own disadvantages. Considering the current uptake of Opzelura and the plans to expand it into the pediatric population as well as globally, it seems that topical JAK inhibitors have a bright future in the evolving treatment paradigm of AD.
References
- Overview of Atopic Dermatitis, AJMC: https://www.ajmc.com/view/overview-of-atopic-dermatitis-article
- GlobalData Atopic Dermatitis Market Forecast: https://www.globaldata.com/media/pharma/atopic-dermatitis-market-exhibit-significant-growth-cagr-10-1-2020-2030-says-globaldata/
- Opzelura Presentation, Incyte: https://investor.incyte.com/static-files/c476a18c-b258-48b9-b8b9-5dfa3a59f46c
- Efficacy and Safety of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis: https://www.karger.com/Article/Pdf/518541
- Incyte Q 2022 Presentation: https://investor.incyte.com/static-files/abdba45a-ed78-4c33-8349-cd327c81a7ba
- Morgan Stanley Analyst Report, February 2022
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